A 29-year-old man presented to the dermatology clinic with a pruritic, erythematous, and scaly rash that had first appeared 2 years earlier. He had sought no medical treatment until this presentation. His medical history included eczema during childhood and seasonal allergies. Physical examination showed erythematous, violaceous plaques that involved more than 90% of the patient’s body-surface area, with some areas that were spared and reflect the baseline appearance of the patient’s skin. What is the diagnosis?

Seborrheic dermatitis The answer is erythrodermic psoriasis. The differential Pityriasis rubra pilaris diagnosis for generalized erythema and plaque formation includes erythrodermic psoriasis, seborrheic Erytherma multiforme dermatitis, and pityriasis rubra pilaris. A punch biopsy specimen obtained from two areas on the back Erythrodermic psoriasis confirmed the diagnosis of erythrodermic psoriasis. An erythrodermic papulosquamous eruption can be Toxic Epidermal Necrolysis associated with an underlying systemic disease. In this case, testing for human immunodeficiency virus (HIV) infection was positive. Psoriatic erythroderma (also known as erythrodermic psoriasis) represents a generalized form of psoriasis that affects all body sites, including the face, hands, feet, nails, trunk, and extremities. First-line treatments for psoriatic erythroderma include immunosuppressive medications such as methotrexate, acitretin, or ciclosporin. Erythroderma is a generalised redness of the skin. It is a very severe skin condition that can be fatal. It can be the result of many inflammatory skin conditions, drugs and malignancies but in a third of cases it is due to psoriasis. Erythrodermic psoriasis may be precipitated by: Infections Low calcium Withdrawal of oral corticosteroids (prednisone) Withdrawal of excessive use of strong topical corticosteroids Strong coal tar preparations Certain medications including lithium, antimalarials and interleukin II Excessive alcohol consumption Erythrodermic psoriasis usually occurs in the setting of known worsening or unstable psoriasis but may uncommonly be the first presentation of psoriasis. Onset can occur acutely over a few days or weeks, or gradually evolve over several months from pre-existing psoriasis. Als Seborrhoisches Ekzem oder Seborrhoische Dermatitis oder Morbus Unna wird ein Hautausschlag (Ekzem) bezeichnet, der besonders auf der Kopfhaut und im Gesicht auftritt und meist mit Schuppungen verbunden ist. Die spezielle Form des Ausschlags bei Neugeborenen ist unter dem volkstümlichen Namen Grind oder Kopfgneis bekannt und wird häufig mit Milchschorf verwechselt oder mit diesem gleichgesetzt. Es entsteht ein Hautausschlag (häufig mit gelblichen Schuppen), der die behaarte Kopfhaut (Gneis) und angrenzende Bereiche, die Haut um die Nase, das Kinn, die Augenbrauen, die Augenlider und die Haut um die Ohren betreffen kann. In schweren Fällen können auch das Brustbein und der Rücken entlang der Wirbelsäule betroffen sein. Ein starker Juckreiz kann auftreten, aber auch völlig fehlen. Durch Kratzen kann die geschwächte Haut verletzt werden und sich zusätzlich entzünden und bluten. Eine zusätzliche bakterielle Besiedlung ist möglich. Die betroffenen Stellen können kosmetisch sehr beeinträchtigen, verheilen aber in aller Regel ohne Narbenbildung. Die Pathogenese des Seborrhoischen Ekzems ist nicht vollständig geklärt. Es werden mehrere Ursachen angenommen. Eine Hauptursache kann eine erhöhte Talgproduktion und die dadurch bedingte Zunahme der Besiedlung mit Malassezia-Hefen sein. Man ging davon aus, dass die Hautausschläge eine Reaktion auf Stoffwechselprodukte des Hefepilzes Malassezia furfur (vormals Pityrosporum ovale genannt) sind. Inzwischen ist bekannt, dass mehrere Malassezia-Hefen beteiligt sind. Die Pityriasis rubra pilaris (auch Stachelflechte oder Devergie-Krankheit) ist eine seltene chronische Hauterkrankung, die von den Haarfollikeln ausgeht. Die Ursache ist unbekannt. Das Aussehen dieser weitgehend schmerzlosen Erkrankung ähnelt dem der Schuppenflechte (Psoriasis). Die Häufigkeit wird mit unter 1 zu 1.000.000 angegeben, die meisten Fälle treten sporadisch auf, es gibt aber auch familiäre Formen (Devergie-Krankheit) mit autosomal- dominantem Erbgang. Der Erkrankung liegen Mutationen im CARD14-Gen am Genort 17q25.3 zugrunde. Nach dem zu Beginn (an Kopfhaut, Armen und Beinen) schubhaften Auftreten von kleinen orangeroten follikulären Papeln (kleine Knötchen) bilden sich gelbrote flächenhafte und manchmal schuppende Herde. Diese können zu einer Rötung der gesamten Haut führen (Erythrodermie). Ferner findet sich eine palmoplantare-Hyperkeratose. Ein typisches Zeichen für die Pityriasis rubra pilaris sind Inseln von nichtbefallener Haut zwischen den Herden. Ohne Therapie besteht die Erkrankung über Jahre, heilt schließlich aber aus. Die Behandlung mit Etretin führt zum Abblassen und Abflachen der Herde innerhalb von wenigen Wochen. Die völlige Heilung dauert jedoch Monate. Erythema (exsudativum) multiforme beschreibt eine akute entzündliche Erkrankung der Haut oder Schleimhaut. Oft tritt diese Hautkrankheit 1–2 Wochen nach einer Infektion auf. Das deutet auf eine immunologische Reaktion hin. Ursache kann auch eine Reaktion auf bestimmte Schadstoffe und Konservierungsmittel (z. B. Triclocarban) sein. Rezidive sind häufig. Es kann auch zu schmerzhaften Schwellungen der Gelenke kommen. Hier hat sich ein Antihistamin (z. B. Fenistil Gel) bewährt.

Es existieren zwei Formen:

Erythema multiforme minor: typische Hautherde mit fehlender/schwacher Blasenkomponente, meist am Handrücken oder Unterarm. Erythema multiforme major: typische Hautherde mit generalisierter mittiger Blasenbildung (Kokarde) inklusive der Füße und Handinnenflächen, diese imponieren als sogenannte „Schießscheibenläsionen“. Es kann zu Erosionen der Mundschleimhaut und schwerem Hautbefall kommen. Auslöser können sowohl verschiedene Viren (z. B. Herpes-simplex- Viren) wie auch verschiedene Arzneimittel sein. Es herrscht ein fließender Übergang zum Stevens- Johnson-Syndrom.

Linderung bringen Kühlung (Kühlpads, feuchte Wickel) und Schmerzmittel. Ggf. kann ein Antiallergikum (z. B. Cetirizin) schnelle Abhilfe schaffen. Das Lyell-Syndrom, auch als Epidermolysis acuta toxica oder Syndrom der verbrühten Haut bezeichnet, ist eine seltene, nach dem schottischen Dermatologen Alan Lyell benannte akute Hautveränderung, die durch blasige Ablösungen der Epidermis der Haut („Syndrom der verbrühten Haut“) gekennzeichnet ist. Die Sterblichkeitsrate beträgt je nach Ausmaß der Schädigung zwischen 25 und 70 %. Es gibt zwei Formen des Lyell-Syndroms. Das medikamentös induzierte Lyell-Syndrom (Toxische epidermale Nekrolyse, TEN) und das staphylogene Lyell-Syndrom (Staphylococcal scalded skin syndrome, SSSS). Das medikamentös induzierte Lyell-Syndrom tritt als zytotoxische allergische Reaktion auf Medikamente insbesondere bei Erwachsenen, seltener bei Kindern auf. Aufgrund der sehr ähnlichen Klinik und Histopathologie kann die TEN als Maximalform des Stevens-Johnson-Syndroms angesehen werden. Folgende Medikamente gelten nach Angaben der Arzneimittelkommission der deutschen Ärzteschaft als mögliche Auslöser: antibakterielle Sulfonamide, zum Beispiel Cotrimoxazol (Mischung aus Sulfamethoxazol und Trimethoprim) Antikonvulsiva, zum Beispiel Phenytoin, Carbamazepin, Lamotrigin Analgetika und nichtsteroidale Antirheumatika, vor allem Pyrazolone wie Metamizol Allopurinol. Das Ovarialkarzinom oder Eierstockkrebs ist eine bösartige Erkrankung der Eierstöcke. Es ist in der westlichen Welt nach dem Endometrium- und dem Zervixkarzinom das dritthäufigste Genitalmalignom der Frau und hat eine schlechtere Prognose als jene. Das mittlere Erkrankungsalter beträgt in Deutschland 69 Jahre, wobei auch wesentlich jüngere Frauen, dann häufig in Zusammenhang mit genetischer Prädisposition, erkranken können. Frauen in Deutschland haben ein Lebenszeitrisiko von 1,5 %, an Eierstockkrebs zu erkranken. Die Inzidenz des Ovarialkarzinoms ist in den letzten 20 Jahren deutlich gesunken, wohingegen die Mortalitätsraten sich auf einem etwa konstanten Niveau bewegen. Von 2005 bis 2009 fielen die alters- und bevölkerungskorrigierten Inzidenzraten bundesweit von 13,5 auf 11,5 Neuerkrankungen pro 100.000 weiblichen Einwohnern und Jahr. Die geschätzten Inzidenzraten für das Jahr 2012 lassen 7.200 Neuerkrankungsfälle erwarten, was einer alters- und bevölkerungskorrigierten Inzidenzrate von 11,0 neuen Fällen pro 100.000 weiblichen Einwohnern entspricht. Die Erkrankung tritt familiär gehäuft auf. Die beiden Gene BRCA1 und BRCA2 spielen (wie beim Brustkrebs) eine Rolle. Kinderlose und Spätgebärende haben gegenüber der Normalbevölkerung ein 2,5-fach erhöhtes Risiko, daran zu erkranken. Hormonelle Kontrazeptiva, häufige Schwangerschaften und langes Stillen sind dagegen protektive Faktoren, da die Eierstöcke durch sie „ruhiggestellt“ werden. Poly(ADP-Ribose)-Polymerase 1 (PARP-1) ist ein körpereigenes Enzym, welches an der DNA- Reparatur beteiligt ist. Die Hemmung des Enzyms führt dazu, dass Brüche in einzelsträngiger DNA (ssDNA) nur noch mithilfe homologer Rekombination behoben werden können. Daher können möglicherweise Krebszellen, bei denen häufig die homologe Rekombination defekt ist, mit Substanzen, die PARP-1 hemmen, abgetötet werden. Der proteolytische Abbau von PARP-1 durch Caspase-3 ist ein Zwischenschritt des programmierten Zelltods (Apoptose). In verschiedenen Spezies ist die Langlebigkeit von Zellen mit der PARP-1-Aktivität korreliert. Auch ist PARP-1 in Neuronen aktiv, die Teil des Langzeitgedächtnisses sind. Im Mausmodell wurde weiterhin gefunden, dass eine Überexpression von PARP-1 und daraus folgender Energiemangel, der Mechanismus für die Toxizität des Streptozotocins für Pankreaszellen ist. PARP-1-freie Mäuse zeigen eine Telomer-Verkürzung und mangelnde Stabilität im gesamten Genom. Die durch PARP-1 katalysierte ADP-Ribosylierung von Chromatinproteinen (wie beispielsweise Histon H1) ist eine bei allen Eukaryoten vorkommende posttranslationale Modifikation, die insbesondere bei DNA-Brüchen in Gang kommt und eine Rolle bei der DNA-Reparatur und der Erholung der Zelle nach Schäden an der DNA spielt. Jeder einzelne Ribosylierungsschritt, von denen etwa 60 bis 80 an einem Acceptor stattfinden, verbraucht ein Molekül NAD+. In reparierten Zellen besteht daher Mangel an dieser Substanz. Olaparib (AZD-2281, trade name Lynparza) is an FDA-approved targeted therapy for cancer. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers. In December 2014, olaparib was approved for use as a single agent by the EMA and the FDA. The FDA approval is for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy. In January 2018, olaparib became the first PARP inhibitor to be approved by the FDA for gBRCAm metastatic breast cancer. Olaparib acts as an inhibitor of the enzyme poly ADP ribose polymerase (PARP), and is termed a PARP inhibitor. BRCA1/2 mutations may be genetically predisposed to development of some forms of cancer, and may be resistant to other forms of cancer treatment. However, these cancers sometimes have a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of benefit if the cancers are susceptible to this treatment. In breast cancer, olaparib is approved for gBRCAm HER2-negative metastatic breast cancer patients who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. If patients have hormone receptor positive cancer, they should have received endocrine therapy where appropriate. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer

Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the oral poly(adenosine diphosphate–ribose) polymerase inhibitor olaparib in relapsed disease has been well established, but the benefit of olaparib as maintenance therapy in newly diagnosed disease is uncertain. We conducted an international, randomized, double-blind, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients with newly diagnosed advanced (International Federation of Gynecology and Obstetrics stage III or IV) high- grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer (or a combination thereof) with a mutation in BRCA1, BRCA2, or both (BRCA1/2) who had a complete or partial clinical response after platinum-based chemotherapy. The patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression- free survival.

Eligible patients had a deleterious or suspected deleterious germline or somatic BRCA1/2 mutation, as determined by local or central testing, with the use of the BRACAnalysis test (Myriad) or, in China, with the use of a BRCA1/2 genetic testing assay (BGI). In the primary analysis, the Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years was 60% in the olaparib group, as compared with 27% in the placebo group (hazard ratio for disease progression or death, 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001) . The median progression-free survival from the end of chemotherapy was 13.8 months in the placebo group.

In the analysis of progression-free survival as assessed by blinded independent central review (data maturity, 38%), the Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years was 69% in the olaparib group, as compared with 35% in the placebo group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.20 to 0.39; P<0.001).

These results are consistent with the benefit of olaparib with regard to progression-free survival as assessed by investigators. In a sensitivity analysis of investigator-assessed progression-free survival that was performed to evaluate for possible attrition bias, the median progression-free survival was approximately 36 months longer in the olaparib group than in the placebo group. In an interim analysis of overall survival (data maturity, 21%), the Kaplan–Meier estimate of the rate of freedom from death at 3 years was 84% in the olaparib group and 80% in the placebo group (hazard ratio for death, 0.95; 95% CI, 0.60 to 1.53). The median time to the first subsequent therapy or death was 51.8 months in the olaparib group and 15.1 months in the placebo group (hazard ratio, 0.30; 95% CI, 0.22 to 0.40). The Kaplan–Meier estimate of the rate of freedom from the use of a second subsequent therapy and from death at 3 years was 74% in the olaparib group and 56% in the placebo group (hazard ratio for the use of a second subsequent therapy or death, 0.45; 95% CI, 0.32 to 0.63), with a median time to the second subsequent therapy or death of 40.7 months in the placebo group. Adverse events were usually managed by dose interruption or dose reduction, rather than discontinuation. The most common adverse events that led to discontinuation were nausea and anemia Acute myeloid leukemia occurred in 3 of 260 patients (1%) in the olaparib group and in none of 130 patients in the placebo group, new primary cancers occurred in 5 (2%) and 3 (2%), respectively, and pneumonitis or interstitial lung disease occurred in 5 (2%) and none.

The mean Trial Outcome Index score at baseline was 73.6 in the olaparib group and 75.0 in the placebo group. The score remained stable in the olaparib group (237 patients), with an adjusted mean change from baseline to 2 years of 0.30 points (95% CI, −0.72 to 1.32), as compared with a change of 3.30 points (95% CI, 1.84 to 4.76) in the placebo group (125 patients). In the phase 3 SOLO1 trial, the use of maintenance therapy with olaparib provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo. Results of a sensitivity analysis and the time to first subsequent therapy or death support an estimated difference in median progression-free survival between the olaparib group and the placebo group of approximately 3 years. The median progression-free survival of 13.8 months in the placebo group, which was measured from the end of chemotherapy rather than from the start of chemotherapy, is consistent with results reported in studies of carboplatin plus paclitaxel in patients with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation. The results of sensitivity analyses and subgroup analyses of progression-free survival were consistent with the results of the primary analysis. The absolute longer progression- free survival with olaparib than with placebo that was seen in a sensitivity analysis in this trial was substantially greater than the increases in progression-free survival that were seen with PARP inhibitors in relapsed disease, and some patients (e.g., those who have platinum resistance) are not eligible to receive olaparib as a second-line therapy. In conclusion, the SOLO1 trial showed that the use of maintenance therapy with olaparib, as compared with placebo, after platinum-based chemotherapy provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation. Implicit in the successful trial by Moore et al. is an unresolved problem in precision oncology. The patients who were enrolled in the trial had “a deleterious or suspected deleterious germline or somatic BRCA1/2 mutation.” Thus, the generalizability of the results of this trial to other populations depends on the definition of “deleterious mutation.” BRCA1 and BRCA2 founder mutations, which were originally identified in the Ashkenazi Jewish population, are generally understood to have deleterious effects. However, the BRCA1/2 genes are very large, and it is not unusual to find nonpathogenic sequence variations in these genes. The complexity arises in the presence of rare variants that have uncertain behavior and are not assigned to the pathogenic group or the nonpathogenic group. These variants may or may not have adverse effects on the function of BRCA1 and BRCA2 gene products. Known as “variants of unknown significance,” these variants do not fall under the binary designation of functional or nonfunctional. Bruton-Tyrosinkinase (BTK) ist ein Enzym in Wirbeltieren, das die Phosphorylierung bestimmter Proteine katalysiert. Es handelt sich daher um eine Kinase. Sie gehört zu den Tyrosinkinasen der Tec-Familie, die vor allem in B-Zellen exprimiert ist. BTK übernimmt wichtige Funktionen bei der Vermittlung des B-Zell-Rezeptor- Signals ins Zellinnere. Eine Mutation im BTK-Gen des Menschen ist Ursache des so genannten Bruton- Syndroms (XLA). Der erste Schritt bei der Aktivierung der Btk ist die Rekrutierung zur Plasmamembran durch die PH-Domäne, die an phosphatidylinostiol-3,4,5-trisphosphat (PIP3) bindet. PIP3 ist ein Produkt der PI3-Kinase. Gleichzeitig ist das Adaptorprotein BLNK wichtig für die Rekrutierung von Btk zur Membran und damit zum B-Zell-Rezeptor. Die Aktivität von Btk in B-Zellen hängt vermutlich von den Kinasen Syk und Lyn ab. Eine wichtige Funktion von Btk ist die Aktivierung der PLCγ2. Btk phosphoryliert dabei die Tyrosine 753 und 759 in PLCγ2, was diese aktiviert. Außerdem rekrutiert Btk phosphatidylinositol-4-phosphate 5 kinase (PIP5K) zur Plasmamembran. PIP5K wiederum synthetisiert das wichtige PLCγ2-Substrat phosphatitylinsitol-4,5- bisphosphate (PIP2) aus PIP. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. Ibrutinib is an irreversible BTK inhibitor that abrogates CLL-related cell signaling, adhesion, proliferation, and homing in vitro and in vivo. Among patients with CLL, treatment with single-agent ibrutinib led to a median progression-free survival of 52 months among those who had relapsed or refractory disease; among those who received ibrutinib as initial treatment, the percentage of patients who were alive and free from disease progression at 2 years was 89%. Ibrutinib has been widely used as an initial treatment for CLL since 2016, when it was approved by the Food and Drug Administration and by the European Medicines Agency for this indication, on the basis of its superiority to chlorambucil. Of the 547 patients who underwent randomization, 524 (96%) were determined to have met the eligibility criteria at screening and were included in the primary analysis. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% (95% confidence interval [CI], 66 to 80) with bendamustine plus rituximab, as compared with 87% (95% CI, 81 to 92) with ibrutinib and 88% (95% CI, 81 to 92) with ibrutinib plus rituximab.

The hazard ratio for disease progression or death was 0.39 (95% CI, 0.26 to 0.58) for the comparison of ibrutinib with bendamustine plus rituximab (one-sided P<0.001) and 0.38 (95% CI, 0.25 to 0.59) for the comparison of ibrutinib plus rituximab with bendamustine plus rituximab (one-sided P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; one-sided P=0.49) The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib- containing regimens (74% with each regimen). Infections occurred in all three treatment groups, with respiratory tract infections, urinary tract infections, sepsis, and abdominal infections being the most common. Atrial fibrillation of any grade occurred in 3% of the patients in the bendamustine-plus-rituximab group, 17% in the ibrutinib group, and 14% in the ibrutinib-plus-rituximab group. Grade 3 or higher hypertension occurred in 14%, 29%, and 34%, respectively. The results of this analysis show the efficacy of treatment with continuous ibrutinib among patients with untreated CLL, but the results also raise the issue of whether indefinite therapy with a BTK inhibitor is needed. The significantly lower rates of undetectable minimal residual disease with the ibrutinib-containing regimens than with bendamustine plus rituximab suggest that treatment with single-agent ibrutinib must be continued indefinitely. Treatments with combined targeted therapies, with the goal of increasing the rate of undetectable minimal residual disease and ultimately discontinuing treatment, have shown promise in early clinical studies and will be evaluated in upcoming NCTN studies. Die Legionärskrankheit wird auch Legionellose oder Legionellen-Pneumonie genannt und ist eine schwere Form der Lungenentzündung. Erstmals wurde die Legionellose 1976 anlässlich einer Tagung der Kriegsveteranenvereinigung „The American Legion" in Philadelphia bekannt, nachdem mehrere Tagungsteilnehmer an einer untypischen Lungenentzündung erkrankten. Während und bis zu zwei Wochen nach der für die Krankheit namensgebenden Tagung erkrankten 221 Männer, von denen 34 starben. Wie später nachgewiesen wurde, waren Bakterien der Art Legionella pneumophila in der Klimaanlage eines Hotels die Verursacher der Epidemie. In Deutschland ist die Zahl der Erkrankungen nach Angaben des Robert Koch-Institutes auf etwa 6.000- 10.000 Fälle pro Jahr zu schätzen. Etwa 2 bis 4% der Lungenentzündungen in Deutschland, die nicht im Krankenhaus erworben wurden, sind auf Legionellen (insbesondere - bis zu 80% - auf Legionella pneumophila) zurückzuführen. Männer erkranken 2 - 3 mal so häufig wie Frauen und hauptsächlich im mittleren Lebensalter. Vor allem bei ansonsten gesunden Menschen verlaufen 90% der Infektionen ohne erkennbare Krankheitszeichen. Es gibt mindestens elf Legionellen-Arten, die dem The Bellevue-Stratford Hotel (Philadelphia, Menschen schaden können und die Legionärskrankheit PA), site of the first known outbreak of verursachen. Von diesen löst Legionella pneumophila am Legionnaires' disease. The hotel closed in häufigsten (80%) Lungenentzündungen aus. Legionellen November, 1976, four months after the lieben Feuchtigkeit und relativ hohe Temperaturen und outbreak. kommen in der Natur im (warmen) Süßwasser vor. Sie treten aber auch in schlecht gewarteten Süßwasseranlagen des Menschen auf - und das dann mitunter in Massen. Die Sphingomonadaceae bilden eine Familie innerhalb der Alphaproteobacteria. Die Bakterien kommen frei in der Natur, z. B. im Boden, marin oder Süßwasser vor. Ein wichtiges Merkmal ist das Vorkommen von Sphingolipiden innerhalb der äußeren Membran der Zellwände. Sphingolipide sind nur in wenigen Gruppen von Bakterien anzutreffen (wie z. B. in den Sphingobakterien), unter den Eukaryonten sind sie aber weit verbreitet. Vor allem in Nervengewebe von Säugetieren sind sie wichtige Bausteine der Zellmembran. Sphingomonadaceae sind auch durch deren Fähigkeit viele verschiedene, teils giftige Aromate abzubauen bekannt. Diese Fähigkeit macht diese Bakterien für Bodensanierungen interessant. Die Vertreter sind stäbchenförmig oder eiförmig. Einige sind pleomorph, d. h. die Zellen verändern die Form im Laufe der Zeit oder je nach Umweltbedingungen. Sphingomonadaceae bilden keine Sporen (asporogen) und zählen zu den gram-negativen Bakterien. Einige Arten sind mit Hilfe von Geißeln beweglich, so ist die Art Sphingomonas adhaesiva polar monotrich begeißelt. Zymomonas ist meist unbegeißelt, aber auch Zellen mit ein bis vier polaren Geißeln treten auf. Bis auf Zymomonas sind alle Arten obligat aerob, sie sind nicht in der Lage ohne Sauerstoff zu leben. Zymomonas hingegen ist fakultativ anaerob bis mikroaerophil, Wachstum ist in Umgebungen mit geringen Mengen von Sauerstoff oder auch unter völlig anoxygenen Bedingungen möglich. Außer bei Zymomonas ist der Stoffwechsel oxidativ (Atmung). Zymomonas hingegen vergärt Zucker (Glucose) zu Alkohol (Ethanol), der Stoffwechselweg ist also die Fermentation (Gärung). Die einzige Art Zymomonas mobilis wird für die alkoholische Gärung des Saftes der Agavenart Agave americana eingesetzt. Der Abbauweg des Zuckers ist nicht, wie zum Beispiel bei den für die Bierbrauerei genutzten Hefen die Glykolyse, sondern der Entner-Doudoroff-Weg. Bei vielen Arten der Sphinomonadaceae können verschiedene Aromate, wie z. B. Anthracen, als einzige Kohlenstoff- und Energiequelle dienen.

Investigation of a Cluster of Sphingomonas koreensis Infections

Plumbing systems are an infrequent but known reservoir for opportunistic microbial pathogens that can infect hospitalized patients. In 2016, a cluster of clinical sphingomonas infections prompted an investigation. We performed whole-genome DNA sequencing on clinical isolates of multidrug-resistant Sphingomonas koreensis identified from 2006 through 2016 at the National Institutes of Health (NIH) Clinical Center. We cultured S. koreensis from the sinks in patient rooms and performed both whole-genome and shotgun metagenomic sequencing to identify a reservoir within the infrastructure of the hospital. These isolates were compared with clinical and environmental S. koreensis isolates obtained from other institutions. Health care–associated infections affect 2 million patients each year in the United States, and an increasing proportion is attributed to multidrug-resistant bacteria.1 Waterborne bacteria represent an important subset of health care–associated pathogens and are of increasing concern to public health authorities. In 2017, the Centers for Medicare and Medicaid Services established stringent requirements for health care facilities to reduce the transmission risk of waterborne organisms from hospital plumbing systems to patients.

Identification of Sphingomonas Cases Sphingomonas Infections at the National Institutes of Health (NIH) Clinical Center, According to Year. The epidemiologic investigation that was initiated when the cluster of sphingomonas infections was identified in 2016 included clinical and microbiologic record review and genomic analysis. Records identified 37 patients from 2001 through 2016 who had sphingomonas species cultured from clinical specimens. Environmental and clinical S. koreensis isolates from geographically distant institutions were solicited for genomic and microbiologic comparisons. A waiver of informed consent was granted by the NIH Office of Human Subjects Research Protection for this study.

Sphingomonas Infections at the National Institutes of Health (NIH) Clinical Center, According to Year. Epidemiologic Investigation Patient records were reviewed for possible common sources of exposure, including hospital rooms, wards, invasive procedures, dialysis, respiratory treatments, and therapeutic baths. Because sphingomonas species reside in aqueous reservoirs, we cultured potable water (100 samples), sink faucets (56 samples), ice machines (7 samples), and other plumbing components (52 samples) from October 2016 through December 2017. Samples were obtained from water and from faucets in the rooms in which inpatients were staying when they acquired S. koreensis infections. Large-volume water samples were also collected from the main municipal intake pipe and its branches, from the heat exchanger, from downstream of the heat exchanger, from the recirculating hot-water loop, and from pipes supplying rooms with known culture-positive sinks. With the aid of plumbers, three culture-positive sinks were disassembled into isolated components, and any visible biofilm and attached pipe segments were cultured. From November 2016 through December 2016, water samples were collected in triplicate from 25 sinks (samples of hot and cold water were collected from 13 manual sinks, and 12 mixed- temperature samples were collected from automatic sinks.) Clinical Characteristics of the Patients From 2006, a year after the opening of a new inpatient hospital building, through 2016, S. koreensis clinical isolates were identified in 12 patients at the NIH Clinical Center. Seven isolates from patients were initially identified only at the genus level, and the species was assigned retrospectively. All the patients were hospitalized at the time of their positive cultures; 5 patients were in the intensive care unit and 7 were in three other wards. The median length of stay was 44 days (range, 0 to 374) before a positive culture was obtained. Four patients had a single positive culture, and the other patients had either persistent or recurrent positive cultures over a range of 2 to 43 days. One isolate per patient was sequenced. Among the 12 patients, 9 were recipients of stem-cell transplants. Eight of the 12 patients had S. koreensis bacteremia, including 2 who had concurrent S. koreensis pneumonia and 3 who had catheter-related bloodstream infections. In addition, 1 patient had pneumonia alone, 1 had cholecystitis that led to peritonitis, and 1 had a deep surgical-site infection. One of the 12 patients had S. koreensis cultured from urine with a low concentration in the absence of pyuria; this patient did not have a urinary tract infection, and the organism was believed to represent contamination or colonization. Of the remaining 11 patients, 8 patients with S. koreensis infections recovered, and 3 patients died (all 3 patients had S. koreensis sepsis as well as severe, unrelated infections). Investigation of Clinical Isolates of Sphingomonas from 2016 Of the six clinical sphingomonas cases in 2016, genomic sequencing classified four as S. koreensis, one as S. yanoikuyae, and one as S. trueperi. The four S. koreensis clinical isolates possessed an exceptionally high degree of genetic similarity (>99.92% average nucleotide identity), which suggested that they belonged to the same clonal strain. These S. koreensis isolates exhibited resistance to multiple classes of antibiotic agents, including aminoglycosides (amikacin and gentamicin), beta-lactams (aztreonam, piperacillin–tazobactam, cefepime, ceftazidime, ceftriaxone, and meropenem), and fluoroquinolones (levofloxacin)., a finding that reflects the difficulty in treating these infections. The isolates were susceptible to trimethoprim– sulfamethoxazole and ciprofloxacin, and therefore these agents were used for treatment. Other sphingomonas clinical isolates were resistant to fewer classes of antibiotics. Aside from a partially conserved chloramphenicol acetyltransferase (catB) gene (96% coverage, 77% identity), no canonical resistance genes could be identified within the S. koreensis genome, a finding that is consistent with intrinsic resistance or undiscovered mechanisms of antibiotic resistance. Genome Comparisons of the Sphingomonas Isolates Obtained from Patients at the NIH Clinical Center.

Phylogenetic Tree of the Sphingomonas koreensis Isolates from the NIH Clinical Center. Metagenomic Sequencing of Multiple S. koreensis Strains Cultured from Sinks in Patient Rooms at the NIH Clinical Center. In 2016, a cluster of sphingomonas infections sparked an epidemiologic investigation that identified 12 patients over 11 years who had been infected with genetically similar strains of S. koreensis, a rarely reported pathogen. Sink faucets and water from numerous patient rooms were positive for S. koreensis, which implicated hospital plumbing infrastructure as a possible reservoir. In this study, genomic and metagenomic techniques provided a higher-resolution understanding of this intermittent cluster and revealed a pervasive reservoir in the water system of the NIH Clinical Center. Whole-genome sequencing of 68 S. koreensis isolates from the NIH Clinical Center (obtained from patients and the plumbing system) revealed a genetically diverse population, a phenomenon increasingly observed in microbial outbreaks. Understanding genetic diversity in an outbreak is of value and can be leveraged to dissect complex issues, such as identification of the point source and patient-to-patient transmission. One limitation of this study is that we could not perfectly match any isolate from a sink in a patient room to a clinical isolate. Matching isolates would have strongly supported S. koreensis transmission, though we would still have been unable to identify the precise modes of transmission from sinks to patients. In addition, we lack metagenomic data for the initial isolates from patients and sinks because we were not aware of strain diversity in early samples. Despite these limitations, a link was found between isolates from one patient and the corresponding room faucet, which were collected 15 days apart. In contrast, other paired patient–sink samples were acquired months and years apart. The heterogeneity among S. koreensis isolates provided a valuable “genetic barcode” to parse subsequent metagenomic samples and to enable the inference of a reservoir at the peripheries of the NIH Clinical Center water-distribution system. Outbreaks of sphingomonas have been reported previously. The ubiquity of this genus in ostensibly clean water makes it a possible hazard to immunocompromised patients. Previous studies have underscored the threat that in-room sinks may pose to patients, from both potable water and splashback from the drain. Als Exom bezeichnet man in der Genetik die Gesamtheit der Exons eines Organismus, also alle Abschnitte, die potenziell Proteine codieren. Das Exom ist nicht abbildbar auf das Transkriptom, da einerseits nicht alle potenziell proteincodierenden Gene auch tatsächlich aktiv sind, andererseits ein Gen zu mehreren verschiedenen RNA-Vorlagen verarbeitet werden kann (Spleißvarianten). In der medizinischen Diagnostik erweist es sich als sinnvoll, anstatt des gesamten Genoms nur das Exom zu sequenzieren, da dort nahezu alle krankheitsverursachenden Mutationen zu finden sind, das menschliche Exom aber nur ein Prozent des Genoms ausmacht. Die Summe aller kodierenden Bereiche des Genoms wird als Exome Sequencing and Variant Analysis Exom bezeichnet. Es umfasst beim Menschen rund 23.000 Genomic DNA was isolated from samples Gene mit ca. 50 Millionen Basen. Beim Whole Exome obtained from patients in accordance with Sequencing (WES) werden alle Exons, d.h. die für Proteine standard protocols, captured with the use of kodierenden Abschnitte im Erbgut, untersucht. Die genetische the Roche or Integrated DNA Technologies Diagnostik fokussiert sich dabei auf diese 1-2 % des (IDT) kit, sequenced on Illumina platforms, menschlichen Genoms, in dem 85 % der bekannten and analyzed with an in-house pipeline to krankheitsverursachenden Mutationen zu finden sind. identify diagnostic variants for patients’ renal Die Exom-Diagnostik besteht entsprechend aus der disease. In brief, we prioritized variants that Sequenzierung des Exoms des Patienten (und gegebenenfalls occurred in a manually curated list of 625 weiterer Angehöriger), der Auswertung der Sequenzdaten und nephropathy-associated genes. and also der Zusammenfassung der Ergebnisse in einem medizinischen evaluated those variants in other mendelian Befund. Diese Diagnostik stellt, insbesondere bei Patienten mit disease–associated genes. Diagnostic komplexer oder unspezifischer Symptomatik und oft jahrelang variants were defined as those that were ungeklärter Diagnose, die Methode der Wahl dar, um die classified as “pathogenic” or “likely Ursache der Erkrankung zu finden. pathogenic” according to the American Die Sequenzierung eines Exoms ist methodisch auch dann College of Medical Genetics and Genomics sinnvoll, wenn kein spezifisches Panel zur Verfügung steht, mit (ACMG) guidelines for clinical sequence der die Symptomatik des Patienten umfassend untersucht interpretation and that were explicative of werden kann. the patient’s nephropathy. Diagnostic Utility of Exome Sequencing for Kidney Disease Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. We performed proband-only exome sequencing in 3315 patients — 1128 patients from A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), a clinical trial involving 2773 patients with end-stage renal disease who were 50 to 80 years of age and were recruited from 280 medical centers in 25 nations, and 2187 patients from the Columbia University Medical Center (CUMC) Genetic Studies of Chronic Kidney Disease, a genetic research and biobanking study recruiting patients who are seen by the CUMC Nephrology Division for the evaluation and management of nephropathy. The clinical diagnosis was classified according to broad etiologic category. For patients in the AURORA cohort, only these broad categories and diagnostic codes for their major clinical features were available; for patients in the CUMC cohort, more detailed clinical information was available from patients’ electronic health records. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 distinct monogenic disorders. Of these patients, 206 (67%) had an autosomal dominant disease, 42 (14%) an autosomal recessive disease, and 54 (18%) an X-linked disease. The remaining 5 of these 307 patients (2%) had dual molecular diagnoses. The 343 diagnostic variants that were detected included 167 protein-truncating variants and 176 nontruncating variants; 202 variants (59%) had been previously reported as pathogenic, and 141 variants (41%) had not at the time of analysis. The majority of diagnostic variants (228 of 343 [66%]) were absent from population control databases. Common Genetic Findings and the Clinical Diagnostic Spectrum.

Of the 66 distinct monogenic disorders detected, 6 accounted for 198 (63%) of the 312 genetic diagnoses: autosomal dominant polycystic kidney disease (ADPKD) due to mutations in PKD1 (75 patients) or PKD2 (22); glomerulopathy due to mutations in COL4A3 (27), COL4A4 (21), or COL4A5 (44); and UMOD- associated tubulointerstitial disease (9). However, the majority of genetic disorders identified (39 of 66 [59%]) were unique to a single patient. Moreover, for 21 genes, diagnostic variants were detected in patients in different clinical categories. For example, only 35 of the 91 patients (38%) with diagnostic variants in COL4A3, COL4A4, or COL4A5 had a clinical diagnosis of the associated disorder (the Alport syndrome or thin basement membrane disease); the remaining 56 patients had clinical diagnoses of focal segmental glomerulosclerosis (15 patients [16%]), unspecified glomerulopathy (20 [22%]) or congenital renal disease (4 [4%]), hypertensive nephropathy (3 [3%]), and nephropathy of unknown origin (14 [15%]). Diagnostic variants were found in 94 of the 619 CUMC patients (15.2%) who had a family history of kidney disease, as compared with 75 of the 1568 patients (4.8%) who did not have one. The diagnostic yield was 7.2% (101 of 1411) among patients with a clinical diagnosis of glomerulopathy, 4.5% (11 of 244) among patients with tubulointerstitial disease, 2.5% (8 of 319) among patients with hypertensive nephropathy, 1.6% (6 of 370) among patients with diabetic nephropathy, and 3.8% (6 of 159) among patients with nephropathy attributed to other causes. Diagnostic yield was higher in the AURORA cohort, which reflected an enrichment for patients with ADPKD; when these patients were excluded, the yield did not differ significantly between the cohorts. Altogether, a family history of kidney disease and a clinical diagnosis of congenital or cystic renal disease and nephropathy of unknown origin were independent predictors of having a genetic diagnosis. In an additional 30 persons (0.9%), we detected putatively diagnostic variants for renal disorders that were not explicative of the patient’s known clinical phenotype. These cases involved dual genetic diagnoses that may contribute to a complex clinical presentation or represent potential phenotypic expansions or clinical misclassification of nephropathy, such as with the putatively pathogenic COL4A3 and COL4A4 variants detected in 7 patients in the AURORA cohort who were reported to have tubulointerstitial disease. These cases would require additional clinical follow-up to reconcile the genetic findings with the reported phenotype. We found the APOL1 risk genotypes28,29 in 100 of the 348 black patients (29%) and 36 of the 485 Hispanic patients (7%), as compared with 173 of 1219 black controls (14%) and 14 of 511 Hispanic controls (3%) (odds ratio for kidney disease among patients with a risk genotype: among black persons, 2.4 [95% confidence interval {CI}, 1.8 to 3.3], P=1.9×10−9; among Hispanic persons, 2.8 [95% CI, 1.5 to 5.8], P=7.5×10−4 [P values calculated by Fisher’s exact test]). The APOL1 risk genotypes were frequently found in patients with clinical diagnoses of glomerulopathy (79 of 363 [22%]), particularly those with a diagnosis of focal segmental glomerulosclerosis (56 of 116 [48%]), hypertensive nephropathy (19 of 81 [23%]), or nephropathy of unknown origin (19 of 78 [24%]). For the 167 patients in the CUMC cohort who had a genetic diagnosis, we used the more detailed clinical data available to assess the diagnostic utility of the genetic findings from exome sequencing and their potential implications for clinical management. For the 167 patients in the CUMC cohort who had a genetic diagnosis, we used the more detailed clinical data available to assess the diagnostic utility of the genetic findings from exome sequencing and their potential implications for clinical management. In the majority of these patients (122 of 167 [73%]), the genetic diagnosis gave new clinical insight. For 65 patients, it enabled identification of a specific underlying cause within the broader category of clinically suspected disease — for example, by pinpointing the precise genetic subtype of focal segmental glomerulosclerosis or cystic disease. In 18 patients, the genetic findings reclassified the disease (e.g., reclassified focal segmental glomerulosclerosis to nephropathy associated with COL4A3, COL4A4, or COL4A5). Finally, exome sequencing identified a molecular cause of nephropathy in 39 patients who had been referred with nephropathy of unknown origin. Other Clinically Relevant Findings We detected pathogenic variants in 16 of the 59 ACMG actionable genes in 34 of the 2187 patients (1.6%) in the CUMC cohort, and review of the electronic health records of these patients revealed that 26 (76%) had a personal or family history of clinical features consistent with the associated disorders. These secondary findings would lead to targeted subspecialty referral and workup, such as oncologic evaluation and mammography for patients with BRCA2 mutations detected. For each patient, these secondary genetic findings also had implications for nephrologic care, such as informing the use of immunosuppression in patients with findings for hereditary cancers or influencing dialysis or diuretic prescriptions for patients who were found to have a genetic predisposition to cardiac arrhythmias. In the present exome-sequencing study involving a diverse, largely adult combined cohort of 3315 patients with chronic kidney disease, we detected diagnostic variants in 307 patients (9.3%). This yield is similar to that observed for cancer, for which genomic diagnostics are routinely used. We identified 66 distinct monogenic disorders, with a high rate of singleton genetic diagnoses and, among the patients with a particular genetic diagnosis, a range of clinical diagnoses. Moreover, we noted diagnostic variants in 48 of the 281 patients (17.1%) with nephropathy of unknown origin, a population that may comprise up to 15% of patients with newly diagnosed end-stage renal disease and for whom traditional diagnostic methods are often unrevealing or contraindicated. Overall, these findings emphasize the high degree of genetic and phenotypic heterogeneity of hereditary nephropathies and show the extent to which genetic testing can help to resolve clinical diagnostic challenges. In the CUMC cohort, for 57 of the 167 cases (34%) reviewed, the genetic findings reclassified disease or provided a cause for undiagnosed nephropathy, emphasizing the usefulness of the “agnostic” approach of exome sequencing, which assesses genes that otherwise may have gone unevaluated with the use of single-gene or phenotype-driven panel testing. We also found that these more targeted approaches would constitute an effective first-line alternative for the patients who had relatively specific clinical presentations, such as ADPKD. Nonetheless, as indicated by the 3 patients who had clinical diagnoses of nephropathy of unknown origin and diagnostic PKD1 variants, broader genetic testing can help resolve atypical cases. Moreover, an analysis involving all 307 patients who had diagnostic variants found by exome sequencing revealed that applying a phenotype- specific panel would resolve, at most, 136 cases (44.3%). Our findings support the diagnostic utility of exome sequencing across different clinical categories of kidney disease and highlight the potential of genetic testing to accurately direct patients to relevant clinical trials and targeted therapies, encouraging similar investigations across other subspecialties. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo (both dopamine-2 receptor antagonists). The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. Effects of Haloperidol, Ziprasidone, and Placebo on Days Alive without Delirium or Coma, Days with Delirium, and Days with Coma. The adjusted median number of days alive without delirium or coma was 8.5 (95% CI, 5.6 to 9.9) in the placebo group, as compared with 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group. The P value for the overall effect across trial groups was 0.26, and therefore, as prespecified in the protocol, no P values were calculated for pairwise comparisons. In adjusted and unadjusted analyses of the active trial-drug groups, as compared with the placebo group, the 95% confidence intervals for the odds ratios included unity for days with delirium and for days with coma during the 14-day intervention period. In analyses of 30-day and 90-day survival as well as time to freedom from mechanical ventilation, ICU discharge, ICU readmission, and hospital discharge, the 95% confidence intervals for the hazard ratios of the effects of haloperidol and ziprasidone, as compared with placebo, included unity.

It would be interesting to know whether hyperactive patients were less likely to injure themselves (e.g., by unplanned endotracheal extubation) when given an active drug as a rescue agent. I would still consider using dopamine antagonists in patients at imminent risk of these types of injurious behaviors, but I would have less confidence in their benefits than I had in the past. Safety End Points

The frequency of excessive sedation, the most common safety end point, did not differ significantly between the trial groups.

Prolongation of the corrected QT interval was more common in the ziprasidone group than in the haloperidol group or placebo group. Torsades de pointes developed in two patients in the haloperidol group during the intervention period, but neither patient had received haloperidol during the 4 days immediately preceding the arrhythmia. One patient in the haloperidol group had the trial drug withheld because of suspected neuroleptic malignant syndrome, but this diagnosis was subsequently ruled out.

Three patients (one in each group) had a trial drug or placebo withheld because of extrapyramidal symptoms, and one patient in the haloperidol group had the trial drug withheld specifically because of dystonia. Effects of Haloperidol, Ziprasidone, and Placebo on 90-Day Survival. For more than 40 years, intravenous antipsychotic medications have been used to treat delirium in hospitalized patients.16,35-39 In an international survey of 1521 intensivists, 65% reported that they treat delirium in the ICU with haloperidol and 53% reported that they treat delirium with atypical antipsychotic medications. In this double-blind, randomized, placebo-controlled trial of intravenous antipsychotic medications for the treatment of delirium in the ICU, there was no evidence that either haloperidol or ziprasidone led to a shorter duration of delirium and coma. Patients who received treatment with up to 20 mg of haloperidol per day or up to 40 mg of ziprasidone per day and those who received placebo had similar outcomes, including survival and lengths of stay in the ICU and hospital. The results of our trial were similar to those of two earlier placebo-controlled trials that examined haloperidol for delirium in smaller numbers of patients in the ICU. In the Modifying the Incidence of Delirium (MIND) trial, 101 patients receiving mechanical ventilation in the ICU were randomly assigned to receive enteral haloperidol, ziprasidone, or placebo; the results showed no significant differences in days alive without delirium or coma. In the Haloperidol Effectiveness in ICU Delirium (Hope-ICU) trial, 142 patients receiving mechanical ventilation in the ICU were randomly assigned to receive intravenous haloperidol or placebo; the results also showed no effect on days alive without delirium or coma, although there were fewer days with agitated delirium in patients who received haloperidol. In conclusion, in this large, double-blind, randomized, placebo-controlled trial, we found no evidence that the use of haloperidol (up to 20 mg daily) or ziprasidone (up 40 mg daily) had an effect on the duration of delirium among patients with acute respiratory failure or shock in the ICU. Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis There is evidence that Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin- lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. Sarcoidosis is an inflammatory disease that is associated with the formation of noncaseating granulomas in one or multiple organ systems. Skin involvement is seen in approximately 25% of patients with sarcoidosis.1 Systemic glucocorticoids are the initial treatment for sarcoidosis with systemic involvement and may be used for the treatment of cutaneous sarcoidosis. Granulomas Clinical Remission of Sarcoidosis with in patients with sarcoidosis are composed primarily of Tofacitinib Therapy. macrophages and T cells. The activation of macrophages in granulomas is considered to be dependent on helper T cells and mediated in part by interferon-γ. Interferon-γ activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway, resulting in the up-regulation of STAT1 transcriptional targets.

Immunohistochemical Testing in the Patient After 10 months of treatment, two skin-lesion samples were obtained from locations that had been previously involved with disease; these samples showed histologic resolution of granulomas. A few histiocytes and lymphocytes were still present, but granulomas were absent. Immunohistochemical stains that had shown pSTAT1 and pSTAT3 in the pretreatment skin-lesion samples indicated a negligible presence of these markers in the skin-lesion samples that were obtained during treatment (immunohistochemical test score for pSTAT1, 18.67 vs. 0.32; immunohistochemical test score for pSTAT3, 3.49 vs. 0.73).

Histologic Remission of Sarcoidosis with Tofacitinib Therapy. RNA Sequencing RNA sequencing was performed on flash-frozen skin-lesion samples, both before and during treatment. These data were compared with publicly available RNA sequencing data from normal human skin. Gene-set enrichment analysis showed activation of interferon-γ and tumor necrosis factor (TNF) α signaling as well as interleukin-6– STAT3 and mammalian target of rapamycin complex 1 (mTORC1) signaling in the pretreatment skin-lesion samples; in contrast, in skin-lesion samples obtained during treatment and in normal skin samples, these pathways did not appear to be activated. While the patient was taking tofacitinib, there was down-regulation of the messenger RNA (mRNA) in the JAK-STAT–dependent pathways (interferon-γ and interleukin-6) as well as of mRNA in pathways that are not directly regulated by JAK-STAT (TNFα and mTORC1). Other proinflammatory transcripts that have been implicated in sarcoidosis pathogenesis, including TLR2, TLR8, IL1B, IL12B, IL18, IL27, CXCL9, and CXCL10, were reduced during tofacitinib therapy.

Levels of pSTAT1 and pSTAT3 in Skin-Lesion Samples from Patients with Cutaneous Sarcoidosis, Xanthelasma, or Normal Skin. Effect of Tofacitinib on Pulmonary Disease During this patient’s 8-year course of different immunomodulatory therapies for her cutaneous sarcoidosis, she underwent interval radiography of the chest that revealed progression of her pulmonary sarcoidosis. Before the initiation of tofacitinib therapy, she had upper lobe–predominant fibrotic lung disease in both lungs and scattered nodules. After 12 months of tofacitinib treatment, CT of the chest revealed persistence of her upper lobe–predominant fibrotic lung disease with peribronchovascular and perilymphatic nodules. At the time of this report, the patient had remained without pulmonary symptoms and has had largely unchanged results on spirometry. A mild impairment in diffusion that was present after 12 months of tofacitinib therapy improved after 18 months of therapy. There are limited therapies for chronic, severe cutaneous sarcoidosis. Glucocorticoids, which have been approved by the Food and Drug Administration for the treatment of pulmonary sarcoidosis, are often used in patients with systemic sarcoidosis and may be used to treat cutaneous disease. The response of a patient with cutaneous sarcoidosis to prednisone is often incomplete, and even when a good response occurs, there are adverse effects associated with long-term use. Evidence for the effectiveness of other therapies for cutaneous sarcoidosis, including methotrexate, TNFα blockers, antimalarial drugs, tetracycline antibiotic agents, thalidomide, and other immunomodulatory agents, is limited and has been derived from small, uncontrolled case series. Our patient’s cutaneous disease did not respond to most of these medications. Treatment with tofacitinib (an inhibitor of JAK1 and JAK3), however, resulted in clinical and histologic remission of cutaneous disease. The withdrawal of treatment resulted in relapse of disease, cutaneous lesions abated after treatment was restarted, and stable clinical remission of her skin disease was observed with ongoing treatment. There was no definite effect on her pulmonary sarcoid. Several studies have shown transcriptional JAK-STAT activation, particularly for STAT1, in sarcoidosis lesions. This was detected in our patient, in whom up-regulation of STAT1 transcripts was seen in the pretreatment skin-lesion sample, and this finding is consistent with the role that is attributed to T-cell–derived interferon-γ in driving macrophage activation in granulomas. The direct inhibition of the interleukin-6–STAT3 pathway, which has also been implicated in sarcoidosis pathogenesis, may also have a role in the response to tofacitinib therapy, on the basis of the RNA sequencing data. The response of cutaneous sarcoidosis to tofacitinib therapy that was observed in our patient needs to be replicated in other patients. Additional studies will be necessary to understand the efficacy and safety of tofacitinib treatment in patients with sarcoidosis and may provide more detailed information about the molecular pathogenesis of this disease. Glucocorticoid-Induced Osteoporosis For the past month, a 75-year-old woman with polymyalgia rheumatica has received prednisone at a dose of 20 mg daily. The treatment plan is to try to taper the dose to 5 mg daily within 6 months. Given typical durations of treatment, the expectation is that she will continue to receive prednisone for 2 years. She is otherwise healthy and has no personal or family history of fracture. She does not smoke or drink alcohol. Her height is 168 cm, and she weighs 68 kg. Her serum 25-hydroxyvitamin D level is 30 ng per milliliter (74 nmol per liter). Her bone mineral density T score is −1.2 at the femoral neck. What would you advise to prevent glucocorticoid-induced osteoporosis and fracture? Approximately 1% of all adults and 3% of adults older than 50 years of age receive glucocorticoids for allergies, inflammatory conditions, or cancer. Long-term use of glucocorticoids is associated with clinically significant toxic effects. Fracture is the most common serious and preventable adverse event associated with these agents. The risk of fracture increases with age and with the dose and duration of glucocorticoid use.

Glucocorticoids have direct and indirect effects on bone remodeling. Bone loss results from increases in expression of receptor activator of nuclear factor-κB ligand (RANKL), which lead to increases in the number of bone-resorbing osteoclasts.4 Osteocyte apoptosis induces osteolysis, which results in an early increased risk of fracture even before bone mineral density decreases. Bone formation also decreases early in glucocorticoid treatment because of a decrease in osteoblast recruitment and accelerated apoptosis. Indirect glucocorticoid effects that also predispose patients to an increased risk of fracture include reduced muscle mass leading to an increased risk of falls, decreases in renal calcium resorption and levels of sex hormones, and alterations in parathyroid hormone pulsatility.

Guidelines Several professional societies have published guidelines for the prevention and management of glucocorticoid-induced osteoporos. Owing to limitations in high-quality data to inform screening and treatment, guidelines vary with respect to the glucocorticoid doses warranting intervention, the need for bone mineral density testing and calcium and vitamin D supplementation, recommendations for pharmacologic treatment, and the thresholds and duration of osteoporosis treatment. The recommendations in this article are consistent with the guidelines of the American College of Rheumatology.

Conclusions and Recommendations The 75-year-old woman with polymyalgia rheumatica described in the vignette is currently receiving prednisone at a dose of more than 7.5 mg per day and is expected to receive a lower dose for the foreseeable future. On the basis of her bone mineral density T score and use of high-dose prednisone, the FRAX 10-year risk of major osteoporotic fracture is 18% and the risk of hip fracture is 3.8% (after increases of 15% and 20%, respectively, in the risk because of use of high-dose prednisone). This level of risk meets American College of Rheumatology guideline criteria for pharmacologic treatment (≥20% risk of major osteoporotic fracture or ≥3% risk of hip fracture). In keeping with these guidelines, we would recommend bisphosphonates (e.g., oral alendronate at a dose of 70 mg once weekly) as first-line treatment. The prednisone dose should be tapered as quickly as possible according to disease activity. We would continue to recommend bisphosphonate treatment for 5 years as long as the patient is taking prednisone at a dose of at least 2.5 mg per day. When the prednisone dose is reduced below 2.5 mg per day, we would reassess the risk of fracture and discontinue bisphosphonate treatment if the predicted risk no longer meets the criteria for pharmacologic treatment. Optimization of calcium and vitamin D intake, weight-bearing exercise, and strategies to prevent falls should be encouraged.

A 47-Year-Old Woman with Recurrent Sinusitis, Cough, and Bronchiectasis

Since her mid-20s, the patient had had recurrent episodes of sinus congestion, with two or three sinus infections annually, which had prompted treatment with multiple courses of antibiotics. When she was approximately 30 years of age, she was evaluated by an otorhinologist at another hospital, who suggested the possibility of an allergic trigger. Skin testing revealed environmental allergies, to dust, grass, and cats. Blood testing revealed allergies to multiple foods, including milk, yeast, wheat, gluten, rye, and egg white. Elimination of milk, grains, and eggs from her diet resulted in a reduction in sinus symptoms for approximately 5 years. However, sinus congestion and sinus infections recurred in subsequent years. Three years before the current evaluation, a persistent cough developed. The patient was evaluated at a second hospital; she received a diagnosis of bacterial pneumonia and was treated. Thereafter, she was referred to a third hospital for sinus surgery with turbinectomy. A sputum culture reportedly grew Enterobacter cloacae, Serratia marcescens, and Mycobacterium abscessus. A complete blood count and results of kidney- and liver-function tests were normal.

The blood level of IgE was normal (5 IU per milliliter; reference range, 0 to 158), as was the alpha1-antitrypsin level (146 mg per deciliter; reference range, 100 to 190). A test for antineutrophil cytoplasmic antibody was negative, as was radioallergosorbent testing for environmental allergens that are common in the northeastern

United States. Pulmonary-function testing reportedly revealed a forced expiratory volume in 1 second (FEV1) of 2.22 liters (80% of the predicted value), a forced vital capacity (FVC) of 2.72 liters (81% of the predicted value), and a ratio of FEV1 to FVC of 82%. The total lung capacity was normal, but the ratio of residual volume to total lung capacity was elevated, at 45% (predicted value, 35%). The diffusion capacity for carbon monoxide was normal. Inhaled fluticasone propionate–salmeterol and levofloxacin were administered, and the cough diminished temporarily. Additional courses of levofloxacin were prescribed for recurrent cough and sputum production during the next 4 months, until the patient was evaluated in the pulmonary clinic of this hospital. The patient appeared to be well and comfortable. The respiratory rate was 14 breaths per minute, and the oxygen saturation 99% while she was breathing ambient air. The height was 165 cm, the weight 64 kg, and the body-mass index (the weight in kilograms divided by the square of the height in meters) 23.5. There was no tenderness on sinus percussion. Crackles were present at the right apex on lung auscultation. There was no clubbing, and the remainder of the examination was normal. Posteroanterior and lateral radiographs of the chest showed “tram track” opacities that involved both upper lung zones and the left lower lung zone, a finding consistent with bronchiectasis. The lung volumes were normal. There was no consolidative opacity or evidence of pulmonary edema, pleural effusion, or mediastinal or hilar lymphadenopathy. Computed tomography (CT) of the chest, performed after the administration of intravenous contrast material, revealed bronchiectasis that involved all lobes of the lung but was most severe in the right upper lobe. Areas of mucous plugging were present in airways in the upper lobes. There were scattered “tree in bud” opacities, as well as multiple scattered solid pulmonary nodules, measuring up to 1.5 cm in diameter. There was no evidence of pulmonary edema, pleural effusion, or mediastinal or hilar lymphadenopathy.

Examination of a sputum sample revealed 3+ to 4+ acid-fast bacilli, along with occasional polymorphonuclear leukocytes and a few gram-positive bacteria.

Bronchiectasis What is bronchiectasis and why did this patient have it? Bronchiectasis is characterized by irreversible damage of the airways that results in dilatation. The pathophysiological event that occurs in all patients with bronchiectasis is chronic inflammation. Although some patients have idiopathic bronchiectasis, which does not have a clear cause, I will focus my differential diagnosis on disorders that cause chronic inflammation of the lung and bronchiectasis, including pulmonary infections, immunodeficiency syndromes, allergies, and disorders that cause impaired airway clearance. Pulmonary Infections Many lung infections can result in the development of bronchiectasis, and several are worth considering in this case. Infection with M. tuberculosis may cause chronic infection and inflammation that results in bronchiectasis. However, this patient had no known exposure to tuberculosis and reported no fever, weight loss, night sweats, or other history suggestive of M. tuberculosis infection. Although examination of a sputum sample was notable for the presence of 3+ to 4+ acid-fast bacilli, I suspect that this finding was associated with nontuberculous mycobacteria, such as M. abscessus, which had been isolated in an earlier sputum culture. Immunodeficiency Syndromes Patients with immunodeficiency syndromes are at high risk for the development of bronchiectasis. Primary immunodeficiency syndromes, such as X-linked agammaglobulinemia and common variable immunodeficiency, are disorders that disrupt normal antibody production, leading to defective humoral immunity and recurrent infections. In X-linked agammaglobulinemia, an autosomal recessive disruption of B-cell development prevents the production of serum antibodies. Allergies Another consideration in this case is an allergic response to fungal spores. In some people, inhalation of Aspergillus fumigatus provokes a brisk allergic response that is characterized by eosinophilia and a high level of IgE antibodies. A hypersensitivity response, known as allergic bronchopulmonary aspergillosis, may ensue, leading to a cycle of bronchial inflammation, mucoid impaction, and bronchial obstruction that results in bronchiectasis. Disorders That Cause Impaired Airway Clearance This patient had a history of recurrent sinus symptoms. Rhinosinusitis is characterized by inflammation of the nose and paranasal sinuses, which can result in nasal congestion, nasal obstruction, rhinorrhea, loss of smell (anosmia), and facial pressure. Given the patient’s long history of chronic rhinosinusitis, the differential diagnosis can be further narrowed to disorders that cause impaired airway clearance. CFTR The diagnosis of cystic fibrosis is based on the presence of clinical signs or symptoms that are consistent with the disease, along with objective evidence of CFTR dysfunction. Guidelines aimed at standardizing the diagnosis were recently updated. The results of sweat chloride testing can be used to confirm the diagnosis, rule out the diagnosis, or prompt further testing, such as genetic testing to identify CFTR mutations. Given the presence of chronic rhinosinusitis, purulent cough, and bronchiectasis, the diagnosis of cystic fibrosis must be considered in this case. Cilia Cilia are hairlike attachments that are found on epithelial surfaces of several cell types. In the respiratory tract, cilia are capable of movement because of nine longitudinal microtubules that are arranged around a central microtubule pair (known as a 9+2 arrangement). The peripheral microtubules have dynein arms, powered by ATP, that slide to produce motion. Ciliary dysfunction is related to short or absent dynein arms on the peripheral microtubules. Primary ciliary dyskinesia is a congenital, autosomal recessive disorder that is characterized by immotile or dyskinetic cilia. Ciliary dysfunction can result in recurrent infections, including otitis media, rhinosinusitis, and pneumonia. In addition to impaired airway clearance, fertility problems can arise in males as a result of impaired spermatozoa motility and in females as a result of impaired ciliary function in the oviduct. It is worth noting that this 47-year-old woman did not have children. In this patient, genetic testing revealed a deletion of phenylalanine at amino acid position 508 (Phe508del) and a substitution of aspartic acid for histidine at position 1152 (D1152H). The identification of these mutations (eine doppelte Heterozygotie) confirms the diagnosis of cystic fibrosis in this patient. In the CFTR2 database, there are 358 patients who are heterozygous for these mutations, which are associated with a relatively mild variant of cystic fibrosis. Ivacaftor ist zur Therapie von Patienten mit der seltenen Erbkrankheit Mukoviszidose indiziert, die eine G551D-Mutation im CFTR-Gen aufweisen. Examination of the histologic slides from the third hospital reveals multifocal abscesses with associated granulomatous inflammation and purulent necrosis. There was multifocal cystic bronchiectasis with dense chronic and acute inflammation, reactive squamous metaplasia, and intraluminal mucopurulent debris. Regions of dense fibrosis with lymphoid aggregates and granulomas were seen in association with bronchiectasis. Overall, the histologic features are most consistent with cystic bronchiectasis complicated by atypical mycobacterial infection. These histologic features are highly consistent with the diagnosis of cystic fibrosis. M. abscessus was again isolated in culture.

This patient has received treatment with ivacaftor since 2017, and the sputum volume has decreased and the percent of predicted FEV1 has stabilized. She remains dependent on oxygen supplementation but has noted a qualitative decrease in dyspnea on exertion. With her meticulous approach to airway clearance and the dedication of her husband, who performs manual percussive therapy twice daily, she has not had an inpatient admission for treatment with intravenous antibiotics for more than 2 years. Since her treatment for M. abscessus, the organisms have not regrown, but she has had persistent growth of M. avium complex, for which she is under continued surveillance. Her course has been further complicated by the development of cystic fibrosis–related diabetes mellitus, the antiphospholipid syndrome, pulmonary embolism, and pulmonary hypertension. She continues to have episodes of hemoptysis. However, in the presence of anticoagulation, nontuberculous mycobacterial infection, and bronchiectasis exacerbation, the cause of hemoptysis is difficult to distinguish. More recently, the patient has begun treatment for cystic fibrosis on the basis of the detected CFTR mutations. The primary defect that is caused by the Phe508del mutation is that the CFTR protein is synthesized but misfolded, which keeps it from reaching the cell surface. This is the target of action of the drugs lumacaftor and tezacaftor. In addition to the Phe508del mutation, the patient had a D1152H mutation, which is considered to be a partial-function mutation that results in diminished ion transport. This type of mutation is the target of the drug ivacaftor, which partially restores ion transport. In the initial trial of ivacaftor, which involved patients with at least one G551D mutation, the average increase in the percent of predicted FEV1 was 10.6 percentage points greater with ivacaftor than with placebo, and patients who received ivacaftor were 55% less likely to have a pulmonary exacerbation in the first 48 weeks than those who received placebo. In 2017, the qualifying mutations for the administration of ivacaftor were expanded to include D1152H, and among patients with such mutations, the average increase in the percent of predicted FEV1 was 2.4 percentage points greater with ivacaftor than with placebo. In 2017, the EXPAND trial showed that treatment with tezacaftor–ivacaftor was associated with greater improvement than treatment with ivacaftor monotherapy among patients who are heterozygous for one Phe508del mutation and one minimal-function mutation (e.g., D1152H), with an average increase in the percent of predicted FEV1 of 6.8 percentage points as compared with 4.7 percentage points. Very recently, phase 2 studies showed that treatment with either VX-659–tezacaftor–ivacaftor or VX-445–tezacaftor–ivacaftor was associated with even greater improvement, with an additional increase of 13 percentage points among patients with one Phe508del mutation and one minimal- function mutation and of 10 percentage points among patients with Phe508del–Phe508del mutations who were already receiving tezacaftor–ivacaftor. Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis What is the association of available medications with long-term pain control in knee osteoarthritis? In this systematic review and network meta-analysis of 33 pharmacological interventions that included 22 037 patients with knee osteoarthritis in 47 randomized clinical trials lasting at least 12 months, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo. RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer. Data at baseline and at the longest available treatment and follow-up of 12 months’ duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta- analysis was performed. The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value. Der WOMAC-Score beinhaltet 24 Fragen und ist in der Lage, die Auswirkungen von Osteoarthritiden des Hüft- und/oder Kniegelenks hinsichtlich dreier Subskalen zu beurteilen:

Schmerz – 5 Fragen Steifigkeit – 2 Fragen Physische Funktion – 17 Fragen

Die WOMAC Likert Version ist ordinalskaliert mit einer Skala von 0 bis 4 (keine, mild, moderat, schwer, extrem). Jede Dimension wird zunächst einzeln berechnet, indem man die Punktewerte der Antwortmöglichkeiten addiert. Somit ergibt sich für die jeweiligen Subskalen folgende Spannweiten der Punkte: Schmerz: 0-20 Punkte Steifigkeit: 0-8 Punkte Physische Funktion: 0-68 Punkte Associations with pain decrease were found for the NSAID celecoxib (SMD, −0.18 [95% CrI, −0.35 to −0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, −0.29 [95% CrI, −0.49 to −0.09]. When the data were analyzed as a mean difference on a normalized scale from 0 to 100, celecoxib was no longer associated with improvement (decrease) in pain (mean difference, −4.93 [95% CrI, −10.23 to 0.30]), but the association of glucosamine sulfate with decreased pain remained (mean difference, −4.07 [95% CrI, −6.99 to −1.18] In this systematic review and network meta-analysis of long-term (≥12 months) trials, celecoxib (an NSAID) and glucosamine sulfate (a symptomatic slow-acting drug in osteoarthritis) were associated with improvement in pain, but the association for celecoxib was small and was no longer observed in a subgroup analysis of high-quality trials. Both celecoxib and glucosamine sulfate were associated with large uncertainty in the estimates compared with placebo. Glucosamine sulfate was associated with improvement in the secondary outcomes of physical function and joint structure.

NSAIDs are the most widely used medications for osteoarthritis. They are associated with a moderate effect on pain compared with placebo or acetaminophen in RCTs with a duration of 12 weeks or less, and are recommended by international guidelines. However, they are recommended for short-term or intermittent use due to safety considerations.87 In the present meta-analysis, celecoxib was the only NSAID associated with long-term pain improvement, but the SMD was small and the association was not observed after trials at high risk of bias were excluded from the analyses, or when the results were based on a scale from 0 to 100.

Glucosamine sulfate was consistently associated with improvement in pain, physical function, and JSN. Other glucosamines were not associated with benefit. This finding is consistent with previously published conventional meta-analyses that mainly included short-term studies. Glucosamine sulfate had a small to moderate effect size.

The combination of intra-articular injections of hyaluronic acid and corticosteroids had a moderately beneficial but highly variable association with pain. A previous conventional meta- analysis showed a different trajectory of intra-articular injections of corticosteroids compared with intra-articular injections of hyaluronic acid for their association with knee osteoarthritis pain improvement. Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors Body fat distribution, usually measured using waist-to-hip ratio (WHR), is an important contributor to cardiometabolic disease independent of body mass index (BMI). Whether mechanisms that increase WHR via lower gluteofemoral (hip) or via higher abdominal (waist) fat distribution affect cardiometabolic risk is unknown. To identify genetic variants associated with higher WHR specifically via lower gluteofemoral or higher abdominal fat distribution and estimate their association with cardiometabolic risk. Genome-wide association studies (GWAS) for WHR combined data from the UK Biobank cohort and summary statistics from previous GWAS (data collection: 2006-2018). Specific polygenic scores for higher WHR via lower gluteofemoral or via higher abdominal fat distribution were derived using WHR- associated genetic variants showing specific association with hip or waist circumference. Associations of polygenic scores with outcomes were estimated in 3 population-based cohorts, a case- cohort study, and summary statistics from 6 GWAS (data collection: 1991-2018). More than 2.4 million common genetic variants (GWAS); polygenic scores for higher WHR (follow-up analyses). Main Outcomes and Measures BMI-adjusted WHR and unadjusted WHR (GWAS); compartmental fat mass measured by dual-energy x-ray absorptiometry, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, fasting glucose, fasting insulin, type 2 diabetes, and coronary disease risk (follow-up analyses). Associations With Compartmental Fat Mass of Polygenic Scores for Higher Waist-to-Hip Ratio (WHR) A, Associations with compartmental fat mass for the 202–genetic variants polygenic score for higher WHR are shown. Associations are reported in clinical or standardized units of continuous outcome per 1-SD increase in body mass index (BMI)–adjusted WHR (corresponding to 0.056 ratio units of age-, sex-, and BMI-residualized WHR in the UK Biobank) due to the polygenic score. The statistical significance threshold for analyses reported in this panel was P < .002. B, Associations with compartmental fat mass for the waist- or hip-specific polygenic scores for higher WHR are shown. Associations were estimated in up to 18 330 individuals of European ancestry in the UK Biobank, Fenland, and EPIC-Norfolk studies. Associations With Cardiometabolic Risk Factors and Disease Outcomes of Waist- or Hip-Specific Polygenic Scores for Higher Waist-to-Hip Ratio (WHR) A, Associations with cardiometabolic risk factors for the waist- or hip-specific polygenic scores for higher WHR are shown. Associations are reported in clinical or standardized units of continuous outcome per 1-SD increase in body mass index (BMI)–adjusted WHR (corresponding to 0.056 ratio units of age-, sex-, and BMI- residualized WHR in the UK Biobank) due to the polygenic score used in a given analysis. Data on blood pressure were from the UK Biobank; data on low-density lipoprotein (LDL-C) and triglyceride levels were from the Global Lipids Genetics Consortium; and data on fasting insulin and fasting glucose were from the Meta- analyses of Glucose and Insulin-Related Traits Consortium. Discussion This large study identified distinct genetic variants associated with a higher WHR via specific associations with lower gluteofemoral or higher abdominal fat distribution. Both of these distinct sets of genetic variants were associated with higher levels of cardiometabolic risk factors and a higher risk of type 2 diabetes and coronary disease. While this study supports the theory that an enhanced accumulation of fat in the abdominal cavity may be a cause of cardiovascular and metabolic disease, it also provides novel evidence of a possible independent role of the relative inability to expand the gluteofemoral fat compartment.

Previous studies of approximately 50 genomic regions associated with BMI-adjusted WHR have shown an association between genetic predisposition to higher WHR and higher risk of cardiometabolic disease, mirroring the well-established BMI-independent association of a higher WHR with incident cardiovascular and metabolic disease in large-scale observational studies. While these results have been widely interpreted as supportive of the role of abdominal fat deposition in cardiometabolic risk independent of overall adiposity, the etiologic contribution of lower levels of gluteofemoral and peripheral fat to these associations has not been considered.

The results of this study support the hypothesis that an impaired ability to preferentially deposit excess calories in the gluteofemoral fat compartment leads to higher cardiometabolic risk in the general population. This is consistent with observations in severe forms of partial lipodystrophy and with the emerging evidence of a shared genetic background between extreme lipodystrophies and fat distribution in the general population.

It has been hypothesized that the association between fat distribution and cardiometabolic risk is due to an enhanced deposition of intra-abdominal fat generating a molecular milieu that fosters abdominal organ insulin resistance.The results of this study support a role of abdominal fat distribution, but they also suggest that impaired gluteofemoral fat distribution may contribute to the relationship between body shape and cardiometabolic health outcomes. Die Telomere (gr. τέλος télos „Ende“ und μέρος méros „Teil“) sind die aus repetitiver DNS und assoziierten Proteinen bestehenden Enden linearer Chromosomen. Die wiederholte Sequenz (Repeatsequenz) und die durch diese Wiederholung bedingte Länge sind in verschiedenen Organismen ähnlich, oft sogar gleich. Bei Wirbeltieren wiederholen sich „Hexanukleotide“, also sechs Nukleotide, mit der Sequenz 5'–TTAGGG–3' mehrere tausend Mal. Telomere sind dementsprechend mehrere Kilo-Basenpaare (kbp) lang. Als wesentliche Strukturelemente stabilisieren diese Endstücke ihr Chromosom. Für den Stabilisierungseffekt ist auch die gefaltete Sekundärstruktur der Telomer-DNA wichtig. Als Barbara McClintock sowie Hermann Joseph Muller gebrochene Chromosomen untersuchten, erkannten sie erstmals, wie wichtig die Enden linearer Chromosomen für deren Stabilität sind. Die beiden amerikanischen Nobelpreisträger sind die Urheber des Begriffes und Wortes Telomer (griechisch für End-Teil). Telomere bewahren beidseits lineare Chromosomen während der Zellzyklen und sind insofern für alle biologischen Vorgänge wichtig. Sie wurden mit dem Altern der Zellen sowie mit deren Immortalisierung und auch mit der Entstehung von Krebs in Zusammenhang gebracht. Die Telomerase wurde 1985 von den beiden Forscherinnen Elizabeth Blackburn und Carol Greider in dem Wimpertierchen Tetrahymenaentdeckt. Sie wurden dafür 2009 mit dem Paul-Ehrlich-Preis und, zusammen mit Jack W. Szostak, mit dem Nobelpreis für Physiologie oder Medizin ausgezeichnet.

Baseline characteristics in a 6-month training study Subjects in the control group were advised to maintain their lifestyle and diet for the next 6months. Subjects in the training groups exercised three times per week for 26weeks.

Aerobic endurance training consisted of 45 min of walking/running at 60% heart rate reserve.

Interval training was performed according to the high- intensity 4x4 method.

Resistance training was a circle training of eight machine-based exercises: back extension, crunch, pull- down, seated row, seated leg curl, seated leg extension, seated chest press, and lying leg press. Twenty repetition maximum (RM) was determined every 6 weeks and training weights were adjusted.

Acute effects of aerobic endurance vs. resistance exercise on telomerase activity. (A) Cross-over comparison of acute regulation of mononuclear cell telomerase activity pre, post, and 24 h after aerobic endurance training (45 min continuous running) and resistance exercise (45 min circle training on eight strength devices) in n = 15 healthy young individuals. Exercise was performed at least 48 h after any previous physical exercise. Telomerase activity of 104 mononuclear cell was compared with human embryonic kidney cells (telomere repeat amplification protocols, TRAP assay). Time course of individual % changes of telomerase activity in 104 magnetic- activated cell sorting-isolated (B) CD14fl and (C) CD34fl leucocyte subfractions compared with pre-exercise in n = 10 healthy young individuals (blue circles: endurance exercise; green circles: resistance exercise).

Cardiac arrest by inhalation of deodorant spray

Case presentation A 19-year-old man was admitted to our hospital after a cardiac arrest. He had been admitted in a drug rehabilitation centre due to cannabis and ketamine abuse. The patient had a history of psychotic symptoms and was therefore placed on the atypical antipsychotic drug aripiprazole. During a hang out with other patients in the clinic, he had placed a towel over his head and inhaled deodorant spray. He became hyperactive jumping up and down and afterwards collapsed. The psychiatric nurses applied basic life support. On arrival of the paramedics, the patient had ventricular fibrillation and was therefore defibrillated. After six defibrillations, there was a return of spontaneous circulation and ST changes were observed on the inferior leads of the ECG On arrival at our emergency department, the patient was intubated. He had a pulse of 88, blood pressure of 133/76, breathing frequency of 20 and saturation of 96%. Physical examination showed no signs of (self) strangulation or other physical trauma. Initial laboratory investigation showed a lactate acidosis.

At arrival on the intensive care unit, the patient was placed on dobutamine, enoximon and nitroglycerine.1 He was sedated with midazolam and remifentanil and therapeutic hypothermia was initiated (33°C during a period of 24 hours) with cold infusion and a Blanketrol III (Cincinnati Sub-Zero Products). On day 2, after reaching normothermia, the ECG had normalised and troponin levels were decreasing. The main toxic substance in deodorant spray inhalation is butane. Butane is one of the hydrocarbons commonly used as propellants in sprayable household products. Hydrocarbons are lipophilic and therefore easily cross the air–blood and blood–brain barrier. It dissolves into tissues with a high fat content such as the nervous system, fat tissue, liver and kidneys. Elimination is through respiration. The longer the carbon chain inhaled the higher the lipophilicity and the lower the onset threshold for the desired experience. Raines et al conducted an electrophysiological study of the effects of butane on the gamma-aminobutyric acid (GABA) receptors and observed butane has the ability to enhance the effects of agonists on the GABA receptor. Thus, butane has similar neurological disinhibiting effect as alcohol. The intention of abusers is to experience feelings of euphoria and disinhibition. Symptoms that can reveal intoxication include slurred speech, ataxia, confusion, hallucinations and a loss of conscious at high blood concentration. Abusers can have a distinct smell on their clothing, skin or breath.